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An overview of the initiation of CSCs. Somatic stem cells (gray) can maintain self-renewal through symmetrical divisions. However, normal stem cells may transform into CSCs (green) under following circumstances including gene mutations occuring in cells during chromatin rearrangements and influence by factors in the tumor microenvironment. On the other hand, differentiated cancer cells (blue) can dedifferentiate into a cancer stem-like cells state by abnormal signal activation or induction from other cells in tumor microenvironment.
Source publication
Over the past 20 years cancer stem cells (CSCs) have been proposed as key players in the tumorigenesis and progression, which are closely related to the initiation, metastasis and therapeutic resistance of cancer. Evidences have been provided that both genetic and epigenetic factors contribute to the regulation of the formation and stemness mainten...
Citations
... Additionally, factors such as hypoxia, cancerassociated fibroblasts, and chronic inflammation in the tumor microenvironment help maintain the stem cell properties of CSCs, making it harder to treat tumors effectively. 35,36 The research on the mechanism of drug resistance of CSCs can guide the development of new targeted therapy for CSCs. Combining targeted therapy for CSCs with conventional treatment methods can eradicate both CSCs and tumor cells simultaneously, enhancing the overall efficacy of tumor treatment. ...
The primary challenge in treating esophageal squamous cell carcinoma (ESCC) is resistance to chemotherapy. Cancer stem cell (CSC) is the root cause of tumor drug resistance. Therefore, targeting CSCs has been considered promising therapeutic strategy for tumor treatment. Here, we report that circMALAT1 was significantly upregulated in ESCC CSC‐like cells and primary tumors from ESCC patients. Clinically, there was a positive correlation between circMALAT1 expression and ESCC stage and lymph node metastasis, as well as poor prognosis for ESCC patients. In vitro and in vivo functional studies revealed that circMALAT1 promoted CSC‐like cells expansion, tumor growth, lung metastasis and drug resistance of ESCC. Mechanistically, circMALAT1 directly interacted with CSC‐functional protein Musashi RNA Binding Protein 2 (MSI2). CircMALAT1 inhibited MSI2 ubiquitination by preventing it from interacting with β‐transducin repeat containing protein (BTRC) E3 ubiquitin ligase. Also, circMALAT1 knockdown inhibited the expression of MSI2‐regulating CSC‐markers c‐Myc in ESCC. Collectively, circMALAT1 modulated the ubiquitination and degradation of the MSI2 protein signaling with ESCC CSCs and accelerated malignant progression of ESCC. CircMALAT1 has the potential to serve as a biomarker for drug resistance and as a target for therapy in CSCs within ESCC.
... PHLDA2 could predict responses to immunotherapy and chemotherapy CSCs are considered to be the cause of treatment resistance [25,26]. So, we continued to investigate the role of PHLDA2 in the treatment of HCC. ...
Hepatocellular carcinoma (HCC) is a malignancy known for its unfavorable prognosis. The dysregulation of the tumor microenvironment (TME) can affect the sensitivity to immunotherapy or chemotherapy, leading to treatment failure. The elucidation of PHLDA2’s involvement in HCC is imperative, and the clinical value of PHLDA2 is also underestimated. Here, bioinformatics analysis was performed in multiple cohorts to explore the phenotype and mechanism through which PHLDA2 may affect the progression of HCC. Then, the expression and function of PHLDA2 were examined via the qRT-PCR, Western Blot, and MTT assays. Our findings indicate a substantial upregulation of PHLDA2 in HCC, correlated with a poorer prognosis. The methylation levels of PHLDA2 were found to be lower in HCC tissues compared to normal liver tissues. Besides, noteworthy associations were observed between PHLDA2 expression and immune infiltration in HCC. In addition, PHLDA2 upregulation is closely associated with stemness features and immunotherapy or chemotherapy resistance in HCC. In vitro experiments showed that sorafenib or cisplatin significantly up-regulated PHLDA2 mRNA levels, and PHLDA2 knockdown markedly decreased the sensitivity of HCC cells to chemotherapy drugs. Meanwhile, we found that TGF-β induced the expression of PHLDA2 in vitro. The GSEA and in vitro experiment indicated that PHLDA2 may promote the HCC progression via activating the AKT signaling pathway. Our study revealed the novel role of PHLDA2 as an independent prognostic factor, which plays an essential role in TME remodeling and treatment resistance in HCC.
... FOSL1 can transform mature cancer cells into stem-like cells that can propagate the tumor by controlling transcription factors related to stemness [90]. FOSL1 regulates SOX2, SALL2, OLIG2, and POU3F2 by binding to their promoter regions and influences a number of stemness indicators [4]. ...
This review specifically examines the important function of the oncoprotein FOSL1 in the dimeric AP-1 transcription factor, which consists of FOS-related components. FOSL1 is identified as a crucial controller of invasion and metastatic dissemination, making it a potential target for therapeutic treatment in cancer patients. The review offers a thorough examination of the regulatory systems that govern the influence exerted on FOSL1. These include a range of changes that occur throughout the process of transcription and after the translation of proteins. We have discovered that several non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a significant role in regulating FOSL1 expression by directly interacting with its mRNA transcripts. Moreover, an investigation into the functional aspects of FOSL1 reveals its involvement in apoptosis, proliferation, and migration. This work involves a comprehensive analysis of the complex signaling pathways that support these diverse activities. Furthermore, particular importance is given to the function of FOSL1 in coordinating the activation of several cytokines, such as TGF-beta, and the commencement of IL-6 and VEGF production in tumor-associated macrophages (TAMs) that migrate into the tumor microenvironment. There is a specific emphasis on evaluating the predictive consequences linked to FOSL1. Insights are now emerging on the developing roles of FOSL1 in relation to the processes that drive resistance and reliance on specific treatment methods. Targeting FOSL1 has a strong inhibitory effect on the formation and spread of specific types of cancers. Despite extensive endeavors, no drugs targeting AP-1 or FOSL1 for cancer treatment have been approved for clinical use. Hence, it is imperative to implement innovative approaches and conduct additional verifications.
... FOSL1 can transform mature cancer cells into stem-like cells that can propagate the tumor by controlling transcription factors related to stemness [88]. FOSL1 regulates SOX2, SALL2, OLIG2, and POU3F2 by binding to their promoter regions and influences a number of stemness indicators [2]. ...
This review centers on the pivotal role of the oncoprotein FOSL1, within the dimeric AP-1 transcription factor consisting of FOS-related elements. FOSL1 emerges as a key regulator governing invasion and metastatic dissemination, therefore making it a promising target for therapeutic intervention in cancer patients. The review provides a comprehensive survey of the regulatory mechanisms that exert influence over FOSL1. These encompass a spectrum of transcriptional and post-translational modifications. Notably, we unveiled the intricate involvement of diverse non-coding RNAs, specifically microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in the modulation of FOSL1 expression through targeted interactions with its mRNA transcripts. Furthermore, an exploration into the functional dimensions of FOSL1 unfolds, encompassing apoptosis, proliferation, and migration. This investigation is accompanied by a thorough examination of the elaborate signaling pathways that underpin these multifaced roles. Additionally, emphasis is placed on the role of FOSL1 in orchestrating the stimulation of various cytokines, including TGF-beta, and the initiation of IL-6 and VEGF production in tumor-associated macrophages (TAMs) that transverse into the tumor microenvironment. A distinct focus is dedicated to appraising the prognostic implications associated with FOSL1. Finally, insights emerge into the evolving roles of FOSL1 in the context of mechanisms governing resistance and dependency on targeted therapeutic modalities.
... However, lack of functional RB is not always sufficient for cell fate reversal. Rather, it is hypothesized that dedifferentiation is achieved through aberrant activation of developmental pathways which regulate stemness and renewal of developing tissues 9,10 . In this vein, loss of Hippo pathway inhibition of its effector, YAP, is associated with dedifferentiation in liver 11,12 , pancreatic 13 , kidney 14 , and colorectal 15 The order in which photoreceptors are recruited to form ommatidia is another important aspect of Drosophila eye development. ...
The RB and Hippo pathways interact to regulate cell proliferation and differentiation. However, their mechanism of interaction is not fully understood. Drosophila photoreceptors with inactivated RB and Hippo pathways specify normally but fail to maintain neuronal identity and dedifferentiate. We performed single-cell RNA-sequencing to elucidate the cause of dedifferentiation and the fate of these cells. We find that dedifferentiated cells adopt a progenitor-like fate due to inappropriate activation of the retinal differentiation suppressor homothorax (hth) by Yki/Sd. This results in activation of the Yki/Hth transcriptional program, driving photoreceptor dedifferentiation. We show that Rbf physically interacts with Yki which, together with the GAGA factor, inhibits hth expression. Thus, RB and Hippo pathways cooperate to maintain photoreceptor differentiation by preventing inappropriate expression of hth in differentiating photoreceptors. Our work accentuates the importance of both RB and Hippo pathway activity for maintaining the state of terminal differentiation.
... However, a proportion of patients with NSCLC develop chemoresistance during treatment, resulting in a less favorable survival profile (4)(5)(6)(7). Cancer stemness is considered the most crucial factor contributing to chemoresistance (8). Therefore, exploring the mechanism underlying chemoresistance and stemness in NSCLC is of great importance. ...
TRPC1 enhances cell proliferation and migration in non-small cell lung cancer (NSCLC); however, its effect on NSCLC chemoresistance and stemness remains to be determined. The aim of the current study was to investigate the effect of TRPC1 on NSCLC chemoresistance and stemness and to determine the underlying mechanism of action. Cisplatin-resistant A549 (A549/CDDP) and H460 (H460/CDDP) cells were first established and were then transfected with negative control small interfering (si)RNA (si-NC) or TRPC1 siRNA (si-TRPC1). Cells were then treated with 740 Y-P, a PI3K/Akt agonist. Subsequently, the sensitivity of A549/CDDP and H460/CDDP cells to CDDP was evaluated. Furthermore, the expression levels of CD133 and CD44, and sphere formation ability were also determined. The results showed that the half-maximal inhibitory concentration (IC50) of CDDP was significantly higher in A549/CDDP cells compared with A549 cells and in H460/CDDP cells compared with H460 cells. TRPC1 silencing decreased the IC50 value of CDDP compared with the si-NC group in A549/CDDP (11.78 vs. 21.58 µM; P<0.01) and H460/CDDP (23.76 vs. 43.11 µM; P<0.05) cells. Additionally, TRPC1 knockdown in both cell lines decreased the number of spheres formed compared with the si-NC group. Furthermore, compared with the si-NC group, A549/CDDP cells transfected with si-TRPC1 exhibited decreased levels of both CD133 (P<0.01) and CD44 (P<0.05). However, only CD133 (P<0.05) was downregulated in TRPC1-depleted H460/CDDP cells compared with the si-NC group. In addition, TRPC1 knockdown repressed PI3K/AKT signaling compared with the si-NC group in both A549/CDDP and H460/CDDP cells (all P<0.05). Finally, cell treatment with 740 Y-P reversed the effect of TRPC1 knockdown on PI3K/AKT signaling, chemoresistance, and cancer stemness in A549/CDDP and H460/CDDP cells (all P<0.05). In conclusion, the results of the current study suggested that targeting TRPC1 could attenuate cancer stemness and chemoresistance via suppression of PI3K/AKT signaling in NSCLC.
... In addition, due to the tumorigenic and invasive activities of CSCs, circRNAs predominantly exert their functions in CSCs [34]. In this study, circRNA 000963 was found to be upregulated in ovarian CSCs, and miRNA candidates (hsa-miR-629-3p, hsa-miR-298, hsa-miR424-5p, hsa-miR-497-5p, and hsa-miR-15b-5p) for GO:0007566 Embryo implantation [4] GO:0061647 Histone H3−K9 modification [4] GO:0016569 Covalent chromatin modification [10] GO:0016570 Histone modification [10] GO:0009894 Regulation of catabolic process [16] GO:0000902 Cell morphogenesis [17] GO:0009653 Anatomical structure morphogenesis [32] GO:0023051 Regulation of signaling [39] GO circRNA 000963 were identified. The KEGG pathway and GO enrichment analyses of the predicted targets of the miRNAs (hsa-miR-629-3p, hsa-miR-298, hsa-miR424-5p, hsa-miR-497-5p, and hsa-miR-15b-5p) showed that they were enriched in signaling pathways regulating pluripotency of stem cells, cell cycle, p53 signaling pathway, PI3K-Akt signaling pathway, Wnt signaling pathway, calcium modulating pathway, G1/S transition of mitotic cell cycle, and miRNA loading onto RNA-induced silencing complex (RISC) involved in gene silencing by miRNA. ...
... In addition, due to the tumorigenic and invasive activities of CSCs, circRNAs predominantly exert their functions in CSCs [34]. In this study, circRNA 000963 was found to be upregulated in ovarian CSCs, and miRNA candidates (hsa-miR-629-3p, hsa-miR-298, hsa-miR424-5p, hsa-miR-497-5p, and hsa-miR-15b-5p) for GO:0007566 Embryo implantation [4] GO:0061647 Histone H3−K9 modification [4] GO:0016569 Covalent chromatin modification [10] GO:0016570 Histone modification [10] GO:0009894 Regulation of catabolic process [16] GO:0000902 Cell morphogenesis [17] GO:0009653 Anatomical structure morphogenesis [32] GO:0023051 Regulation of signaling [39] GO circRNA 000963 were identified. The KEGG pathway and GO enrichment analyses of the predicted targets of the miRNAs (hsa-miR-629-3p, hsa-miR-298, hsa-miR424-5p, hsa-miR-497-5p, and hsa-miR-15b-5p) showed that they were enriched in signaling pathways regulating pluripotency of stem cells, cell cycle, p53 signaling pathway, PI3K-Akt signaling pathway, Wnt signaling pathway, calcium modulating pathway, G1/S transition of mitotic cell cycle, and miRNA loading onto RNA-induced silencing complex (RISC) involved in gene silencing by miRNA. ...
... Ovarian cancer cells A2780 and SKOV3 were purchased from American Type Culture Collection (ATCC, GO:0008631 Intrinsic apoptotic signaling pathway in response to oxidative stress [2] GO:1904377 Positive regulation of protein localization to cell periphery [2] GO:0006413 Translational initiation [3] GO:0006446 Regulation of translational initiation [3] GO:0090630 Activation of GTPase activity [3] GO:0097191 Extrinsic apoptotic signaling pathway [3] GO:0097190 Apoptotic signaling pathway [5] GO:0007049 Cell cycle [10] GO:0044267 Cellular protein metabolic process [20] GO:0044260 Cellular macromolecule metabolic process [28] 0 GO:0008080 N−acetyltransferase activity [2] GO:0008135 Translation factor activity, RNA binding [2] GO:0032813 Tumor necrosis factor receptor superfamily binding [2] GO:0034212 Peptide N−acetyltransferase activity [2] GO:0045182 Translation regulator activity [3] GO:0090079 Translation regulator activity, nucleic acid binding [3] GO:0140030 Modification−dependent protein binding [3] GO:0003714 Transcription corepressor activity [4] GO:0016740 Transferase activity [13] GO:0005515 Protein binding [39] 0 Sphere-forming cells, CSCs, were prepared from A2780 and SKOV3 cells, as previously described [38]. In brief, for the isolation of sphere-forming cells, A2780 and SKOV3 cells were detached with trypsin/EDTA solution medium (Thermo Scientific, Waltham, MA, USA) and seeded in CSC culture medium containing with Neurobasal ™ medium (Thermo Scientific, Waltham, MA, USA) supplemented with 20 ng/ ml basic fibroblast growth Factor ...
Background
Circular RNAs (circRNAs) are noncoding RNAs that regulate miRNA expression; however, their functions in cancer stem cells (CSCs) are not well known.
Methods
To determine the function of differentially expression of circRNAs associated with ovarian CSCs, circRNA profiling was conducted using a circRNA-based microarray on sphere-forming cells derived from A2780 and SKOV3 epithelial ovarian cancer cells termed A2780-SP and SKOV3-SP compared to monolayer cells such as A2780 and SKOV3 cells, respectively. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the biological functions of the circRNAs expressed in CSCs.
Results
The circRNA-based microarray data showed that 159 circRNAs were significantly upregulated (fold change > 1.5) and 55 circRNAs were downregulated in ovarian CSCs compared to monolayer cells. GO and KEGG enrichment analysis of differentially expressed circRNAs in ovarian CSCs showed that they were mainly involved in cell cycle, histone modification, cellular protein metabolic process, cell cycle, apoptotic signaling pathway, and ubiquitin-mediated proteolysis in ovarian cancer. In addition, the hsa-circRNA000963-miRNA-mRNA regulatory network was constructed based on potential target of miRNAs. These analyses involved that the biological function of the hsa-circRNA00096/miRNA/mRNA network was involved in signaling pathways regulating pluripotency of stem cells, PI3K-Akt signaling pathway, cell cycle, p53 signaling pathway, Wnt signaling pathway, calcium modulating pathway, and production of miRNAs involved in gene silencing by miRNA.
Conclusions
Our data demonstrate the expression profiles of circRNAs in ovarian CSCs and suggest that circRNAs may be potential diagnostic and predictive biomarkers of ovarian cancer.
... The term cancer stem cell (CSC) characterizes a subpopulation of cancer cells with an intrinsic self-renewal and tumorigenic capacity, mirrored by their significant role in tumor development, therapy resistance, relapse, and metastasis [199]. The pathways responsible for establishing a CSC phenotype are diverse and differ among cancer entities [200]. In breast cancer cells, the most important pathways for this process are STAT, Hedgehog, protein kinase C (PKC), MAPK, Notch, and Hippo, with hundreds of downstream genes responsible for enhanced stemness [201]. ...
Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Adipose tissue is the major microenvironment of breast cancer. Obesity changes the composition, structure, and function of adipose tissue, which is associated with inflammation and metabolic dysfunction. Interestingly, adipose tissue is rich in ASCs/MSCs, and obesity alters the properties and functions of these cells. As a key component of the mammary stroma, ASCs play essential roles in the breast cancer microenvironment. The crosstalk between ASCs and breast cancer cells is multilateral and can occur both directly through cell–cell contact and indirectly via the secretome released by ASC/MSC, which is considered to be the main effector of their supportive, angiogenic, and immunomodulatory functions. In this narrative review, we aim to address the impact of obesity on ASCs/MSCs, summarize the current knowledge regarding the potential pathological roles of ASCs/MSCs in the development of breast cancer, discuss related molecular mechanisms, underline the possible clinical significance, and highlight related research perspectives. In particular, we underscore the roles of ASCs/MSCs in breast cancer cell progression, including proliferation and survival, angiogenesis, migration and invasion, the epithelial–mesenchymal transition, cancer stem cell development, immune evasion, therapy resistance, and the potential impact of breast cancer cells on ASCS/MSCs by educating them to become cancer-associated fibroblasts. We conclude that ASCs/MSCs, especially obese ASCs/MSCs, may be key players in the breast cancer microenvironment. Targeting these cells may provide a new path of effective breast cancer treatment.
... Rapid progression, cancer recurrence, and treatment resistance are the leading causes of the depraved GBM prognosis [3]; therefore, exploring treatment options to inhibit cancer progression, recurrence, and restore treatment sensitivity has never ceased. In addition, cancer stem cells (CSCs) are recently observed to relate to a high risk of recurrence and resistance to treatment in many cancers, including GBM [19][20][21]. Therefore, observing potential targets for repressing tumor progression and cancer stemness is necessary. ...
... For instance, AKIP1 promotes cell proliferation, invasion, and EMT in vitro and increases metastasis in vivo in gastric cancer via modifying Slug [23]; meanwhile, AKIP1 knockdown significantly suppresses cell migration and invasion by blocking Akt/GSK-3β/Snail pathway in breast cancer patients [22]. In addition, AKIP1 induces tumor metastasis and early recurrence in hepatocellular carcinoma via facilitating Wnt/β-catenin/CBP pathway [21]. In the present study, we observed that AKIP1 significantly enhanced cell invasion meanwhile reducing cell apoptosis and increased cell proliferation to some extent in GBM cell lines, as explanations below: (1) AKIP1 promoted a variety of malignant invasion-related genes and pathways, such as NF-κB, AKT, Wnt/β-catenin/CBP, GSK-3β/Snail, and thus improved the GBM cell invasion. ...
... Only one clinical study revealed that AKIP1 was associated with poor pathological differentiation in nonsmall cell lung cancer patients [24]. Furthermore, some studies found that AKIP1 was related to EMT, drug resistance, cancer metastasis, and recurrence [7,[21][22][23], which were the key features of CSCs or cancer stemness. These imply that AKIP1 might be involved in the regulation of cancer stemness. ...
Background
A-kinase interacting protein 1 (AKIP1) is recently implicated in the pathogenesis of several solid tumors, while its role in glioblastoma multiforme (GBM) is largely unknown. Therefore, the current study aimed to investigate the effect of AKIP1 on GBM cell malignant behaviors, stemness, and its underlying molecular mechanisms.
Methods
U-87 MG and A172 cells were transfected with control or AKIP1 overexpression plasmid; control or AKIP1 siRNA plasmid. Then cell proliferation, apoptosis, invasion, CD133⁺ cell proportion, and sphere formation assays were performed. Furthermore, RNA-Seq was performed in U-87 MG cells. Besides, AKIP1 expression was detected in 25 GBM and 25 low-grade glioma (LGG) tumor samples.
Results
AKIP1 was increased in several GBM cell lines compared to the control cell line. After transfections, it was found that AKIP1 overexpression increased cell invasion, CD133⁺ cell proportion, and sphere formation ability while less affecting cell proliferation or cell apoptosis in U-87 MG and A172 cells. Moreover, AKIP1 siRNA achieved the opposite effect in these cells, except that it inhibited cell proliferation but induced cell apoptosis to some extent. Subsequent RNA-Seq assay showed several critical carcinogenetic pathways, such as PI3K/AKT, Notch, EGFR tyrosine kinase inhibitor resistance, Ras, ErbB, mTOR pathways, etc. were potentially related to the function of AKIP1 in U-87 MG cells. Clinically, AKIP1 expression was higher in GBM tissues than in LGG tissues, which was also correlated with the poor prognosis of GBM to some degree.
Conclusions
AKIP1 regulates the malignant behaviors and stemness of GBM via regulating multiple carcinogenetic pathways.
... (Figure 2). Besides these data, a large body of research describes the microenvironment fundamental for forming CSCs' niche and their secretome that promotes abnormal neo-vasculature formation, and paracrine signals responsible for resistance to standard cancer treatments [103,104]. To develop effective new therapies, the possibility of targeting tissue stiffness and the ECM could represent an important goal in cancer treatment and should be evaluated. ...
Simple Summary
Cancer is one of the most debated problems all over the world. Cancer stem cells are considered responsible of tumor initiation, metastasis, drug resistance, and recurrence. This subpopulation of cells has been found into the tumor bulk and showed the capacity to self-renew, differentiate, up to generate a new tumor. In the last decades, several studies have been set on the molecular mechanisms behind their specific characteristics as the Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, etc. The most powerful part of CSCs is represented by the niches as “promoter” of their self-renewal and “protector” from the common oncological treatment as chemotherapy and radiotherapy. In our review article we highlighted the primary mechanisms involved in CSC tumorigenesis for the setting of further targets to control the metastatic process.
Abstract
Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.
